bims-medebr 2023-07-23 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2023‒07‒23
23 papers selected by
Regina F. Fernández
Johns Hopkins University

Axonal energy metabolism, and the effects in aging and neurodegenerative diseases.
Monoacylglycerol Lipase Inhibition Prevents Short-Term Mitochondrial Dysfunction and Oxidative Damage in Rat Brain Synaptosomal/Mitochondrial Fractions and Cortical Slices: Role of Cannabinoid Receptors.
Effects of sodium lactate infusion in two teenagers with Glucose Transporter 1 Deficiency Syndrome.
Acute effects of single and repeated mild traumatic brain injury on levels of neurometabolites, lipids, and mitochondrial function in male rats.
Decreased DHA-containing phospholipids in the neocortex of dementia with Lewy bodies are associated with soluble Aβ42 , phosphorylated α-synuclein, and synaptopathology.
Mass Spectrometry in Cerebrospinal Fluid Uncovers Association of Glycolysis Biomarkers with Alzheimer's Disease in a Large Clinical Sample.
Validating MALDI-IMS Feasibility in Ex Vivo Brain Slices.
Mitochondrial dysfunction following repeated mild blast traumatic brain injury is attenuated by a mild mitochondrial uncoupling prodrug.
Neuroprotective effect of a medium-chain triglyceride ketogenic diet on MPTP-induced Parkinson's disease mice: a combination of transcriptomics and metabolomics in the substantia nigra and fecal microbiome.
Fatty acid oxidation organizes mitochondrial supercomplexes to sustain astrocytic ROS and cognition.
Lipid in microglial biology - from material to mediator.
Regional contributions of D-serine to Alzheimer's disease pathology in male AppNL-G-F/NL-G-F mice.
Lipin knockdown in pan-neuron of Drosophila induces reduction of lifespan, deficient locomotive behavior, and abnormal morphology of motor neuron.
Do astrocytes act as immune cells after pediatric TBI?
Protein concentrations and activities of fatty acid desaturase and elongase enzymes in liver, brain, testicle, and kidney from mice: Substrate dependency.
S-Nitrosylation-mediated dysfunction of TCA cycle enzymes in synucleinopathy studied in postmortem human brains and hiPSC-derived neurons.
Mitochondria-derived peptide SHLP2 regulates energy homeostasis through the activation of hypothalamic neurons.
Evidence of Disturbed Insulin Signaling in Animal Models of Alzheimer's Disease.
APOE ε4 allele, along with G206D-PSEN1 mutation, alters mitochondrial networks and their degradation in Alzheimer's disease.
Characterization of N-glycome profile in mouse brain tissue regions by MALDI-TOF/MS.
Plasma membrane of focal adhesions has a high content of cholesterol and phosphatidylcholine with saturated acyl chains.
Ldlr-/-.Leiden mice develop neurodegeneration, age-dependent astrogliosis and obesity-induced changes in microglia immunophenotype which are partly reversed by complement component 5 neutralizing antibody.
Succinic semialdehyde dehydrogenase deficiency in mice and in humans: an untargeted metabolomics perspective.

Mol Neurodegener. 2023 Jul 20. 18(1): 49

Axonal energy metabolism, and the effects in aging and neurodegenerative diseases.

Sen Yang, Jung Hyun Park, Hui-Chen Lu.

  Human studies consistently identify bioenergetic maladaptations in brains upon aging and neurodegenerative disorders of aging (NDAs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis. Glucose is the major brain fuel and glucose hypometabolism has been observed in brain regions vulnerable to aging and NDAs. Many neurodegenerative susceptible regions are in the topological central hub of the brain connectome, linked by densely interconnected long-range axons. Axons, key components of the connectome, have high metabolic needs to support neurotransmission and other essential activities. Long-range axons are particularly vulnerable to injury, neurotoxin exposure, protein stress, lysosomal dysfunction, etc. Axonopathy is often an early sign of neurodegeneration. Recent studies ascribe axonal maintenance failures to local bioenergetic dysregulation. With this review, we aim to stimulate research in exploring metabolically oriented neuroprotection strategies to enhance or normalize bioenergetics in NDA models. Here we start by summarizing evidence from human patients and animal models to reveal the correlation between glucose hypometabolism and connectomic disintegration upon aging/NDAs. To encourage mechanistic investigations on how axonal bioenergetic dysregulation occurs during aging/NDAs, we first review the current literature on axonal bioenergetics in distinct axonal subdomains: axon initial segments, myelinated axonal segments, and axonal arbors harboring pre-synaptic boutons. In each subdomain, we focus on the organization, activity-dependent regulation of the bioenergetic system, and external glial support. Second, we review the mechanisms regulating axonal nicotinamide adenine dinucleotide (NAD+) homeostasis, an essential molecule for energy metabolism processes, including NAD+ biosynthetic, recycling, and consuming pathways. Third, we highlight the innate metabolic vulnerability of the brain connectome and discuss its perturbation during aging and NDAs. As axonal bioenergetic deficits are developing into NDAs, especially in asymptomatic phase, they are likely exaggerated further by impaired NAD+ homeostasis, the high energetic cost of neural network hyperactivity, and glial pathology. Future research in interrogating the causal relationship between metabolic vulnerability, axonopathy, amyloid/tau pathology, and cognitive decline will provide fundamental knowledge for developing therapeutic interventions.

Keywords:  Aging; Axonal bioenergetics; Axonopathy; Energy metabolism; Glucose; Glycolysis; Mitochondria; NAD; Neurodegeneration; Neuroprotection

DOI:  https://doi.org/10.1186/s13024-023-00634-3
Neurotox Res. 2023 Jul 17.

Monoacylglycerol Lipase Inhibition Prevents Short-Term Mitochondrial Dysfunction and Oxidative Damage in Rat Brain Synaptosomal/Mitochondrial Fractions and Cortical Slices: Role of Cannabinoid Receptors.

Karen Jaqueline Paredes-Ruiz, Karla Chavira-Ramos, Sonia Galvan-Arzate, Edgar Rangel-López, Çimen Karasu, Isaac Túnez, Anatoly V Skalny, Tao Ke, Michael Aschner, Mario Orozco-Morales, Ana Laura Colín-González, Abel Santamaría.

  Inhibition of enzymes responsible for endocannabinoid hydrolysis represents an invaluable emerging tool for the potential treatment of neurodegenerative disorders. Monoacylglycerol lipase (MAGL) is the enzyme responsible for degrading 2-arachydonoylglycerol (2-AG), the most abundant endocannabinoid in the central nervous system (CNS). Here, we tested the effects of the selective MAGL inhibitor JZL184 on the 3-nitropropinic acid (3-NP)-induced short-term loss of mitochondrial reductive capacity/viability and oxidative damage in rat brain synaptosomal/mitochondrial fractions and cortical slices. In synaptosomes, while 3-NP decreased mitochondrial function and increased lipid peroxidation, JZL184 attenuated both markers. The protective effects evoked by JZL184 on the 3-NP-induced mitochondrial dysfunction were primarily mediated by activation of cannabinoid receptor 2 (CB2R), as evidenced by their inhibition by the selective CB2R inverse agonist JTE907. The cannabinoid receptor 1 (CB1R) also participated in this effect in a lesser extent, as evidenced by the CB1R antagonist/inverse agonist AM281. In contrast, activation of CB1R, but not CB2R, was responsible for the protective effects of JZL184 on the 3-NP-iduced lipid peroxidation. Protective effects of JZL184 were confirmed in other toxic models involving excitotoxicity and oxidative damage as internal controls. In cortical slices, JZL184 ameliorated the 3-NP-induced loss of mitochondrial function, the increase in lipid peroxidation, and the inhibition of succinate dehydrogenase (mitochondrial complex II) activity, and these effects were independent on CB1R and CB2R, as evidenced by the lack of effects of AM281 and JTE907, respectively. Our novel results provide experimental evidence that the differential protective effects exerted by JZL184 on the early toxic effects induced by 3-NP in brain synaptosomes and cortical slices involve MAGL inhibition, and possibly the subsequent accumulation of 2-AG. These effects involve pro-energetic and redox modulatory mechanisms that may be either dependent or independent of cannabinoid receptors' activation.

Keywords:  Endocannabinoid system; JTE907; JZL184; Mitochondrial dysfunction; Monoacylglycerol lipase inhibition; Oxidative damage

DOI:  https://doi.org/10.1007/s12640-023-00661-4
Neuropediatrics. 2023 Jul 21.

Effects of sodium lactate infusion in two teenagers with Glucose Transporter 1 Deficiency Syndrome.

Loes Annet van Gemert, Nens van Alfen, Lizzy van Gaal, Saskia B Wortmann, Michel Willemsen.

Glucose is an important fuel for the brain. In Glucose Transporter 1 Deficiency Syndrome (GLUT1DS) the transport of glucose across the blood-brainbarrier is limited. Most individuals with GLUT1DS present with developmental problems, epilepsy, and (paroxysmal) movement disorders, and respond favorably to the ketogenic diet. Similar to ketones, lactate is an alternative energy source for the brain. The aim of this study is to investigate whether intravenous infusion of sodium lactate in children with GLUT1DS has beneficial effects on their epilepsy. We performed a proof of principle study with two subjects with GLUT1DS who were not on a ketogenic diet and suffered from abscense epilepsy. After overnight fasting, sodium lactate (600 mmol/l) was infused during 120 minutes, under video-EEG recording and monitoring of or serum lactate, glucose, electrolytes and pH. Furthermore, the EEGs were compared with pre-/postprandial EEGs of both subjects, obtained shortly before the study. Fasting EEGs of both subjects showed frequent bilateral, frontocentral poly-spike-and-wave complexes. In one subject no more epileptic discharges were seen postprandially and after the start of lactate infusion. The EEG of the other subject did not change, neither postprandially nor after lactate infusion. Serum pH, lactate and sodium changed temporary during the study. This study suggests that sodium lactate infusion is possible in individuals with GLUT1DS, and may have potential therapeutic effects. Cellular abnormalities, beyond neuronal energy failure, may contribute to the underlying disease mechanisms of GLUT1DS, explaining explain why not all individuals respond to the supplementation of alternative energy sources.

DOI: https://doi.org/10.1055/a-2134-8766
Front Mol Neurosci. 2023 ;16 1208697

Acute effects of single and repeated mild traumatic brain injury on levels of neurometabolites, lipids, and mitochondrial function in male rats.

Josh Allen, Louise Pham, Simon T Bond, William T O'Brien, Gershon Spitz, Sandy R Shultz, Brian G Drew, David K Wright, Stuart J McDonald.

  Introduction: Mild traumatic brain injuries (mTBIs) are the most common form of acquired brain injury. Symptoms of mTBI are thought to be associated with a neuropathological cascade, potentially involving the dysregulation of neurometabolites, lipids, and mitochondrial bioenergetics. Such alterations may play a role in the period of enhanced vulnerability that occurs after mTBI, such that a second mTBI will exacerbate neuropathology. However, it is unclear whether mTBI-induced alterations in neurometabolites and lipids that are involved in energy metabolism and other important cellular functions are exacerbated by repeat mTBI, and if such alterations are associated with mitochondrial dysfunction.Methods: In this experiment, using a well-established awake-closed head injury (ACHI) paradigm to model mTBI, male rats were subjected to a single injury, or five injuries delivered 1 day apart, and injuries were confirmed with a beam-walk task and a video observation protocol. Abundance of several neurometabolites was evaluated 24 h post-final injury in the ipsilateral and contralateral hippocampus using in vivo proton magnetic resonance spectroscopy (1H-MRS), and mitochondrial bioenergetics were evaluated 30 h post-final injury, or at 24 h in place of 1H-MRS, in the rostral half of the ipsilateral hippocampus. Lipidomic evaluations were conducted in the ipsilateral hippocampus and cortex.
Results: We found that behavioral deficits in the beam task persisted 1- and 4 h after the final injury in rats that received repetitive mTBIs, and this was paralleled by an increase and decrease in hippocampal glutamine and glucose, respectively, whereas a single mTBI had no effect on sensorimotor and metabolic measurements. No group differences were observed in lipid levels and mitochondrial bioenergetics in the hippocampus, although some lipids were altered in the cortex after repeated mTBI.
Discussion: The decrease in performance in sensorimotor tests and the presence of more neurometabolic and lipidomic abnormalities, after repeated but not singular mTBI, indicates that multiple concussions in short succession can have cumulative effects. Further preclinical research efforts are required to understand the underlying mechanisms that drive these alterations to establish biomarkers and inform treatment strategies to improve patient outcomes.

Keywords:  MRI; behavior; biomarker; concussion; lipids; mitochondria; proton magnetic resonance spectroscopy

DOI:  https://doi.org/10.3389/fnmol.2023.1208697
Brain Pathol. 2023 Jul 18. e13190

Decreased DHA-containing phospholipids in the neocortex of dementia with Lewy bodies are associated with soluble Aβ42 , phosphorylated α-synuclein, and synaptopathology.

Joyce R Chong, Yuek Ling Chai, Huayang Xing, Deron R Herr, Markus R Wenk, Paul T Francis, Clive Ballard, Dag Aarsland, David L Silver, Christopher P Chen, Amaury Cazenave-Gassiot, Mitchell K P Lai.

  Docosahexaenoic acid (DHA) is an essential omega-3 polyunsaturated fatty acid implicated in cognitive functions by promoting synaptic protein expression. While alterations of specific DHA-containing phospholipids have been described in the neocortex of patients with Alzheimer's disease (AD), the status of these lipids in dementia with Lewy bodies (DLB), known to manifest aggregated α-synuclein-containing Lewy bodies together with variable amyloid pathology, is unclear. In this study, post-mortem samples from the parietal cortex of 25 DLB patients and 17 age-matched controls were processed for phospholipidomics analyses using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) platform. After controlling for false discovery rate, six out of the 46 identified putative DHA-phospholipid species were significantly decreased in DLB, with only one showing increase. Altered putative DHA-phospholipid species were subsequently validated with further LC-MS/MS measurements. Of the DHA-containing phospholipid (DCP) species showing decreases, five negatively correlated with soluble beta-amyloid (Aβ42) levels, whilst three also correlated with phosphorylated α-synuclein (all p < 0.05). Furthermore, five of these phospholipid species correlated with deficits of presynaptic Rab3A, postsynaptic neurogranin, or both (all p < 0.05). Finally, we found altered immunoreactivities of brain lysolipid DHA transporter, MFSD2A, and the fatty acid binding protein FABP5 in DLB parietal cortex. In summary, we report alterations of specific DCP species in DLB, as well as their associations with markers of neuropathological burden and synaptopathology. These results support the potential role of DHA perturbations in DLB as well as therapeutic targets.

Keywords:  beta-amyloid; dementia with Lewy bodies; docosahexaenoic acid; neocortex; synaptopathology; α-synuclein

DOI:  https://doi.org/10.1111/bpa.13190
Res Sq. 2023 Jun 27. pii: rs.3.rs-3073597. [Epub ahead of print]

Mass Spectrometry in Cerebrospinal Fluid Uncovers Association of Glycolysis Biomarkers with Alzheimer's Disease in a Large Clinical Sample.

Matthijs B de Geus, Shannon N Leslie, TuKiet Lam, Weiwei Wang, Pia Kivisakk, Angus C Nairn, Steven E Arnold, Becky C Carlyle.

Background Alzheimer's disease (AD) is a complex heterogenous neurodegenerative disorder, characterized by multiple pathophysiologies, including disruptions in brain metabolism. Defining markers for patient stratification across these pathophysiologies is an important step towards personalized treatment of AD. Efficient brain glucose metabolism is essential to sustain neuronal activity, but hypometabolism is consistently observed in AD. The molecular changes underlying these observations remain unclear. Recent studies have indicated dysregulation of several glycolysis markers in AD cerebrospinal fluid and tissue. Methods In this study, unbiased mass spectrometry was used to perform a deep proteomic survey of cerebrospinal fluid (CSF) from a large-scale clinically complex cohort to uncover changes related to impaired glucose metabolism. Results Two glycolytic enzymes, Pyruvate kinase (PKM) and Aldolase A (ALDOA) were found to be specifically upregulated in AD CSF compared to other non-AD groups. Presence of full-length protein of these enzymes in CSF was confirmed through immunoblotting. Levels of tryptic peptides of these enzymes correlated significantly with CSF glucose and CSF lactate in matching CSF samples. Conclusions The results presented here indicate a general dysregulation of glucose metabolism in the brain in AD. We highlight two markers ALDOA and PKM that may act as potential functionally-relevant biomarkers of glucose metabolism dysregulation in AD.

DOI: https://doi.org/10.21203/rs.3.rs-3073597/v1
J Am Soc Mass Spectrom. 2023 Jul 20.

Validating MALDI-IMS Feasibility in Ex Vivo Brain Slices.

Nikita Ollen-Bittle, Chloe A Lowry, Katherine E Donovan, R David Andrew, Shawn N Whitehead.

Matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS) generates unique mass spectra in X/Y coordinates across a tissue sample, thus allowing for the spatial detection and relative quantification of biologic compounds in situ. The soft ionization of MALDI-IMS makes it an ideal technique for high-resolution imaging of complex lipid species. Lipid-based spatial chemical maps derived from MALDI-IMS provide critical insight into the unique molecular profiles of a variety of neurologic diseases. Ex vivo brain slice preparations are a prominent alternative to in vivo animal models for studying many different neurologic conditions. For the first time, we present a feasible protocol for achieving reproducible lipidomic MALDI-IMS data from ex vivo rat brain slices and provide evidence that ex vivo brain slices maintain spatiochemical lipidomic profiles representative of an intact whole brain. We conducted a methods comparison assessing the lipid profiles within the neocortex, striatum, and corpus callosum between coronal sections taken from ex vivo brain slices and the current gold standard tissue preparation method, fresh frozen whole brains. For the first time we demonstrate a technique by which 400 μm ex vivo brain slices can be extracted from an imaging chamber and prepared for MALDI-IMS in a way that preserves their lipidomic integrity. We demonstrate the feasibility of MALDI-IMS in ex vivo brain slices and provide a roadmap for MALDI-IMS utilization in uncharted neuroscience fields.

DOI: https://doi.org/10.1021/jasms.3c00152
J Neurotrauma. 2023 Jul 21.

Mitochondrial dysfunction following repeated mild blast traumatic brain injury is attenuated by a mild mitochondrial uncoupling prodrug.

William Brad Hubbard, Hemendra Vekaria, Gopal Velmurugan, Olivia Kalimon, Paresh Prajapati, Emily Brown, John Geisler, Patrick G Sulllivan.

  Mild traumatic brain injury (mTBI) results in impairment of brain metabolism, which is propagated by mitochondrial dysfunction in the brain. Mitochondrial dysfunction has been identified as a pathobiological therapeutic target to quell cellular dyshomeostasis. Further, therapeutic approaches targeting mitochondrial impairments, such as mild mitochondrial uncoupling, have been shown to alleviate behavioral alterations after TBI. To examine how mild mitochondrial uncoupling modulates acute mitochondrial outcomes in a military-relevant model of mTBI, we utilized repeated blast overpressure of 11psi peak overpressure to model repeated mild blast traumatic brain injury (rmbTBI) in rats followed by assessment of mitochondrial respiration and mitochondrial-related oxidative damage at 2d post-rmbTBI. Treatment groups were administered 8 or 80 mg/kg MP201, a prodrug of 2,4 dinitrophenol (DNP) that displays improved pharmacokinetics compared to its metabolized form. Synaptic and glia-enriched mitochondria were isolated using fractionated mitochondrial magnetic separation technique. There was a consistent physiological response, decreased heart rate, following mbTBI among experimental groups. While there was a lack of injury effect in mitochondrial respiration of glia-enriched mitochondria, there were impairments in mitochondrial respiration in synaptic mitochondria isolated from the prefrontal cortex (PFC) and the amygdala/entorhinal/piriform cortex (AEP) region. Impairments in synaptic mitochondrial respiration were rescued by oral 80 mg/kg MP201 treatment after rmbTBI, which may be facilitated by increases in complex II and complex IV activity. Mitochondrial oxidative damage in glia-enriched mitochondria was increased in the PFC and hippocampus after rmbTBI. MP201 treatment alleviated elevated glia-enriched mitochondrial oxidative damage following rmbTBI. However, there was a lack of injury-associated differences in oxidative damage in synaptic mitochondria. Overall, our report demonstrates that rmbTBI results in mitochondrial impairment diffusely throughout the brain and mild mitochondrial uncoupling can restore mitochondrial bioenergetics and oxidative balance.

Keywords:  METABOLISM; MILITARY INJURY; MITOCHONDRIA; OXIDATIVE STRESS; TRAUMATIC BRAIN INJURY

DOI:  https://doi.org/10.1089/neu.2023.0102
Cell Death Discov. 2023 Jul 17. 9(1): 251

Neuroprotective effect of a medium-chain triglyceride ketogenic diet on MPTP-induced Parkinson's disease mice: a combination of transcriptomics and metabolomics in the substantia nigra and fecal microbiome.

Wenlong Zhang, Shiyu Chen, Xingting Huang, Huichun Tong, Hongxin Niu, Lingli Lu.

The ketogenic diet (KD) is a low carbohydrate and high-fat protein diet. It plays a protective role in neurodegenerative diseases by elevating the levels of ketone bodies in blood, regulating central and peripheral metabolism and mitochondrial functions, inhibiting neuroinflammation and oxidative stress, and altering the gut microbiota. However, studies on ketogenic therapy for Parkinson's disease (PD) are still in their infancy. Therefore, we examined the possible protective effect of KD in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model, examined the mouse gut microbiota and its metabolites, and performed transcriptomics and metabolomics on the substantia nigra of mice. Our results showed that a long-term medium-chain triglyceride KD (MCT-KD) significantly reduced MPTP-induced damage to dopaminergic (DA) neurons, exerted antioxidant stress through the PI3K/Akt/Nrf2 pathway, and reversed oxidative stress in DA neurons. The MCT-KD also reduced mitochondrial loss, promoted ATP production, and inhibited the activation of microglia to protect DA neurons in MPTP-induced PD mice. MCT-KD altered the gut microbiota and consequently changed the metabolism of substantia nigra neurons through gut microbiota metabolites. Compared to the MPTP group, MCT-KD increased the abundance of gut microbiota, including Blautia and Romboutsia. MCT-KD also affects purine metabolism in the substantia nigra pars compacta (SNpc) by altering fecal metabolites. This study shows that MCT-KD has multiple protective effects against PD.

DOI: https://doi.org/10.1038/s41420-023-01549-0
Nat Metab. 2023 Jul 17.

Fatty acid oxidation organizes mitochondrial supercomplexes to sustain astrocytic ROS and cognition.

Brenda Morant-Ferrando, Daniel Jimenez-Blasco, Paula Alonso-Batan, Jesús Agulla, Rebeca Lapresa, Dario Garcia-Rodriguez, Sara Yunta-Sanchez, Irene Lopez-Fabuel, Emilio Fernandez, Peter Carmeliet, Angeles Almeida, Marina Garcia-Macia, Juan P Bolaños.

Having direct access to brain vasculature, astrocytes can take up available blood nutrients and metabolize them to fulfil their own energy needs and deliver metabolic intermediates to local synapses1,2. These glial cells should be, therefore, metabolically adaptable to swap different substrates. However, in vitro and in vivo studies consistently show that astrocytes are primarily glycolytic3-7, suggesting glucose is their main metabolic precursor. Notably, transcriptomic data8,9 and in vitro10 studies reveal that mouse astrocytes are capable of mitochondrially oxidizing fatty acids and that they can detoxify excess neuronal-derived fatty acids in disease models11,12. Still, the factual metabolic advantage of fatty acid use by astrocytes and its physiological impact on higher-order cerebral functions remain unknown. Here, we show that knockout of carnitine-palmitoyl transferase-1A (CPT1A)-a key enzyme of mitochondrial fatty acid oxidation-in adult mouse astrocytes causes cognitive impairment. Mechanistically, decreased fatty acid oxidation rewired astrocytic pyruvate metabolism to facilitate electron flux through a super-assembled mitochondrial respiratory chain, resulting in attenuation of reactive oxygen species formation. Thus, astrocytes naturally metabolize fatty acids to preserve the mitochondrial respiratory chain in an energetically inefficient disassembled conformation that secures signalling reactive oxygen species and sustains cognitive performance.

DOI: https://doi.org/10.1038/s42255-023-00835-6
Inflamm Regen. 2023 Jul 17. 43(1): 38

Lipid in microglial biology - from material to mediator.

Shota Yamamoto, Takahiro Masuda.

  Microglia are resident macrophages in the central nervous system (CNS) that play various roles during brain development and in the pathogenesis of CNS diseases. Recently, reprogramming of cellular energetic metabolism in microglia has drawn attention as a crucial mechanism for diversification of microglial functionality. Lipids are highly diverse materials and crucial components of cell membranes in every cell. Accumulating evidence has shown that lipid and its metabolism are tightly involved in microglial biology. In this review, we summarize the current knowledge about microglial lipid metabolism in health and disease.

Keywords:  CNS; Lipid; Macrophage; Microglia

DOI:  https://doi.org/10.1186/s41232-023-00289-z
Front Aging Neurosci. 2023 ;15 1211067

Regional contributions of D-serine to Alzheimer's disease pathology in male AppNL-G-F/NL-G-F mice.

Xiance Ni, Ran Inoue, Yi Wu, Tomoyuki Yoshida, Keisuke Yaku, Takashi Nakagawa, Takashi Saito, Takaomi C Saido, Keizo Takao, Hisashi Mori.

  Background: Neurodegenerative processes in Alzheimer's disease (AD) are associated with excitotoxicity mediated by the N-methyl-D-aspartate receptor (NMDAR). D-Serine is an endogenous co-agonist necessary for NMDAR-mediated excitotoxicity. In the mammalian brain, it is produced by serine racemase (SRR) from L-serine, suggesting that dysregulation of L-serine, D-serine, or SRR may contribute to AD pathogenesis.Objective and methods: We examined the contributions of D-serine to AD pathology in the AppNL-G-F/NL-G-F gene knock-in (APPKI) mouse model of AD. We first examined brain SRR expression levels and neuropathology in APPKI mice and then assessed the effects of long-term D-serine supplementation in drinking water on neurodegeneration. To further confirm the involvement of endogenous D-serine in AD progression, we generated Srr gene-deleted APPKI (APPKI-SRRKO) mice. Finally, to examine the levels of brain amino acids, we conducted liquid chromatography-tandem mass spectrometry.
Results: Expression of SRR was markedly reduced in the retrosplenial cortex (RSC) of APPKI mice at 12 months of age compared with age-matched wild-type mice. Neuronal density was decreased in the hippocampal CA1 region but not altered significantly in the RSC. D-Serine supplementation exacerbated neuronal loss in the hippocampal CA1 of APPKI mice, while APPKI-SRRKO mice exhibited attenuated astrogliosis and reduced neuronal death in the hippocampal CA1 compared with APPKI mice. Furthermore, APPKI mice demonstrated marked abnormalities in the cortical amino acid levels that were partially reversed in APPKI-SRRKO mice.
Conclusion: These findings suggest that D-serine participates in the regional neurodegenerative process in the hippocampal CA1 during the amyloid pathology of AD and that reducing brain D-serine can partially attenuate neuronal loss and reactive astrogliosis. Therefore, regulating SRR could be an effective strategy to mitigate NMDAR-dependent neurodegeneration during AD progression.

Keywords:  Alzheimer’s disease; D-serine; amino acid homeostasis; excitotoxicity; neurodegeneration; serine racemase

DOI:  https://doi.org/10.3389/fnagi.2023.1211067
Neuroreport. 2023 Aug 02. 34(12): 629-637

Lipin knockdown in pan-neuron of Drosophila induces reduction of lifespan, deficient locomotive behavior, and abnormal morphology of motor neuron.

Yen D H Nguyen, Hideki Yoshida, Thanh Men Tran, Kaeko Kamei.

The Lipin family is evolutionarily conserved among insects and mammals, and its crucial roles in lipid synthesis and homeostatic control of energy balance have been well documented. This study investigated the function of Lipin in neuronal function and neurodegeneration. The GAL4/UAS system was used to knock down Lipin in the nervous system of Drosophila and investigate its behavioral and cellular phenotypes. The neuromuscular junction (NMJ) morphology was detected by immunostaining. Moreover, triacylglycerol and ATP levels were analyzed by using assay Kit. This study found that Lipin is localized almost in the cytoplasm of neurons in the brain lobe and ventral nerve cord, which are part of the central nervous system (CNS) of Drosophila melanogaster. Lipin knockdown larvae exhibit decreased locomotor activity, aberrant morphology of motor nerve terminals at NMJs, and reduced number and size of lipid droplets in the CNS. Furthermore, neuron-specific knockdown of Lipin leads to locomotor defects and a shortened lifespan, accompanied by a reduction in ATP levels in the adult stage. These results indicate that Lipin plays a crucial role in the CNS of Drosophila.

DOI: https://doi.org/10.1097/WNR.0000000000001936
Neurobiol Dis. 2023 Jul 17. pii: S0969-9961(23)00246-2. [Epub ahead of print] 106231

Do astrocytes act as immune cells after pediatric TBI?

Polina E Panchenko, Lea Hippauf, Jan-Pieter Konsman, Jerome Badaut.

  Astrocytes are in contact with the vasculature, neurons, oligodendrocytes and microglia, forming a local network with various functions critical for brain homeostasis. One of the primary responders to brain injury are astrocytes as they detect neuronal and vascular damage, change their phenotype with morphological, proteomic and transcriptomic transformations for adaptive response. The role of astrocytic responses in brain dysfunction is not fully elucidated in adult, and even less described in the developing brain. Children are vulnerable to traumatic brain injury (TBI), which represents a leading cause of death and disability in the pediatric population. Pediatric brain trauma, even with mild severity, can lead to long-term health complications, such as cognitive impairments, emotional disorders and social dysfunction later in life. To date, the underlying pathophysiology is still not fully understood. In this review, we focus on the astrocytic response in pediatric TBI and propose a potential immune role of the astrocyte in response to trauma. We discuss the contribution of astrocytes in the local inflammatory cascades and secretion of various immunomodulatory factors involved in the recruitment of local microglial cells and peripheral immune cells through cerebral blood vessels. Taken together, we propose that early changes in the astrocyte phenotype can alter normal development of the brain, with long-term consequences on neurological outcomes, as described in preclinical models and patients.

Keywords:  Astrocyte; Blood-brain barrier; Cytokines; Inflammation; Microglia; Neurovascular unit; Pediatric traumatic brain injury; Preclinical models

DOI:  https://doi.org/10.1016/j.nbd.2023.106231
Biofactors. 2023 Jul 20.

Protein concentrations and activities of fatty acid desaturase and elongase enzymes in liver, brain, testicle, and kidney from mice: Substrate dependency.

Rodrigo Valenzuela, Adam H Metherel, Giulia Cisbani, Mackenzie E Smith, Raphaël Chouinard-Watkins, Brinley J Klievik, Luis A Videla, Richard P Bazinet.

  The synthesis rates of n-3 and n-6 polyunsaturated fatty acids (PUFAs) in rodents and humans are not agreed upon and depend on substrate availability independently of the capacity for synthesis. Therefore, we aimed to assess the activities of the enzymes for n-3 and n-6 PUFA synthesis pathways in liver, brain, testicle, kidney, heart, and lung, in relation to their protein concentration levels. Eight-week-old Balb/c mice (n = 8) were fed a standard chow diet (6.2% fat, 18.6% protein, and 44.2% carbohydrates) until 14 weeks of age, anesthetized with isoflurane and tissue samples were collected (previously perfused) and stored at -80°C. The protein concentration of the enzymes (Δ-6D, Δ-5D, Elovl2, and Elovl5) were assessed by ELISA kits; their activities were assayed using specific PUFA precursors and measuring the respective PUFA products as fatty acid methyl esters by gas chromatographic analysis. The liver had the highest capacity for PUFA biosynthesis, with limited activity in the brain, testicles, and kidney, while we failed to detect activity in the heart and lung. The protein concentration and activity of the enzymes were significantly correlated. Furthermore, Δ-6D, Δ-5D, and Elovl2 have a higher affinity for n-3 PUFA precursors compared to n-6 PUFA. The capacity for PUFA synthesis in mice mainly resides in the liver, with enzymes having preference for n-3 PUFAs.

Keywords:  elongase 2; elongase 5; enzymatic activity; polyunsaturated fatty acids; protein concentration; Δ-5 desaturase; Δ-6 desaturase

DOI:  https://doi.org/10.1002/biof.1992
Cell Chem Biol. 2023 Jul 04. pii: S2451-9456(23)00196-4. [Epub ahead of print]

S-Nitrosylation-mediated dysfunction of TCA cycle enzymes in synucleinopathy studied in postmortem human brains and hiPSC-derived neurons.

Paschalis-Thomas Doulias, Hongmei Yang, Alexander Y Andreyev, Nima Dolatabadi, Henry Scott, Charlene K Raspur, Parth R Patel, Tomohiro Nakamura, Steven R Tannenbaum, Harry Ischiropoulos, Stuart A Lipton.

A causal relationship between mitochondrial metabolic dysfunction and neurodegeneration has been implicated in synucleinopathies, including Parkinson disease (PD) and Lewy body dementia (LBD), but underlying mechanisms are not fully understood. Here, using human induced pluripotent stem cell (hiPSC)-derived neurons with mutation in the gene encoding α-synuclein (αSyn), we report the presence of aberrantly S-nitrosylated proteins, including tricarboxylic acid (TCA) cycle enzymes, resulting in activity inhibition assessed by carbon-labeled metabolic flux experiments. This inhibition principally affects α-ketoglutarate dehydrogenase/succinyl coenzyme-A synthetase, metabolizing α-ketoglutarate to succinate. Notably, human LBD brain manifests a similar pattern of aberrantly S-nitrosylated TCA enzymes, indicating the pathophysiological relevance of these results. Inhibition of mitochondrial energy metabolism in neurons is known to compromise dendritic length and synaptic integrity, eventually leading to neuronal cell death. Our evidence indicates that aberrant S-nitrosylation of TCA cycle enzymes contributes to this bioenergetic failure.

DOI: https://doi.org/10.1016/j.chembiol.2023.06.018
Nat Commun. 2023 07 19. 14(1): 4321

Mitochondria-derived peptide SHLP2 regulates energy homeostasis through the activation of hypothalamic neurons.

Seul Ki Kim, Le Trung Tran, Cherl NamKoong, Hyung Jin Choi, Hye Jin Chun, Yong-Ho Lee, MyungHyun Cheon, ChiHye Chung, Junmo Hwang, Hyun-Ho Lim, Dong Min Shin, Yun-Hee Choi, Ki Woo Kim.

Small humanin-like peptide 2 (SHLP2) is a mitochondrial-derived peptide implicated in several biological processes such as aging and oxidative stress. However, its functional role in the regulation of energy homeostasis remains unclear, and its corresponding receptor is not identified. Hereby, we demonstrate that both systemic and intracerebroventricular (ICV) administrations of SHLP2 protected the male mice from high-fat diet (HFD)-induced obesity and improved insulin sensitivity. In addition, the activation of pro-opiomelanocortin (POMC) neurons by SHLP2 in the arcuate nucleus of the hypothalamus (ARC) is involved in the suppression of food intake and the promotion of thermogenesis. Through high-throughput structural complementation screening, we discovered that SHLP2 binds to and activates chemokine receptor 7 (CXCR7). Taken together, our study not only reveals the therapeutic potential of SHLP2 in metabolic disorders but also provides important mechanistic insights into how it exerts its effects on energy homeostasis.

DOI: https://doi.org/10.1038/s41467-023-40082-7
Neurosci Biobehav Rev. 2023 Jul 19. pii: S0149-7634(23)00295-6. [Epub ahead of print] 105326

Evidence of Disturbed Insulin Signaling in Animal Models of Alzheimer's Disease.

Suélen Santos Alves, Gabriel Servilha-Menezes, Leticia Rossi, Rui Milton Patrício da Silva Junior, Norberto Garcia-Cairasco.

  Since glucose reuptake by neurons is mostly independent of insulin, it has been an intriguing question whether insulin has or not any roles in the brain. Consequently, the identification of insulin receptors in the central nervous system has fueled investigations of insulin functions in the brain. It is also already known that insulin can influence glucose reuptake by neurons, mostly during activities that have the highest energy demand. The identification of high density of insulin receptors in the hippocampus also suggests that insulin may present important roles related to memory. In this context, studies have reported worse performance in cognitive tests among diabetic patients. In addition, alterations in the regulation of central insulin pathways have been observed in the brains of Alzheimer's disease (AD) patients. In fact, some authors have proposed AD as a third type of diabetes and recently, our group proposed insulin resistance as a common link between different AD hypotheses. Therefore, in the present narrative review, we intend to revise and gather the evidence of disturbed insulin signaling in experimental animal models of AD.

Keywords:  AD animal models; Alzheimer’s Disease; biomarkers; insulin resistance; memory; metabolism

DOI:  https://doi.org/10.1016/j.neubiorev.2023.105326
Front Aging Neurosci. 2023 ;15 1087072

APOE ε4 allele, along with G206D-PSEN1 mutation, alters mitochondrial networks and their degradation in Alzheimer's disease.

Irene Costa-Laparra, Elena Juárez-Escoto, Carlos Vicario, Rosario Moratalla, Patricia García-Sanz.

  Introduction: Alzheimer's disease remains the most common neurodegenerative disorder, depicted mainly by memory loss and the presence in the brain of senile plaques and neurofibrillary tangles. This disease is related to several cellular alterations like the loss of synapses, neuronal death, disruption of lipid homeostasis, mitochondrial fragmentation, or raised oxidative stress. Notably, changes in the autophagic pathway have turned out to be a key factor in the early development of the disease. The aim of this research is to determine the impact of the APOE allele ε4 and G206D-PSEN1 on the underlying mechanisms of Alzheimer's disease.Methods: Fibroblasts from Alzheimer's patients with APOE 3/4 + G206D-PSEN1 mutation and homozygous APOE ε4 were used to study the effects of APOE polymorphism and PSEN1 mutation on the autophagy pathway, mitochondrial network fragmentation, superoxide anion levels, lysosome clustering, and p62/SQSTM1 levels.
Results: We observed that the APOE allele ε4 in homozygosis induces mitochondrial network fragmentation that correlates with an increased colocalization with p62/SQSTM1, probably due to an inefficient autophagy. Moreover, G206D-PSEN1 mutation causes an impairment of the integrity of mitochondrial networks, triggering high superoxide anion levels and thus making APOE 3/4 + PSEN1 fibroblasts more vulnerable to cell death induced by oxidative stress. Of note, PSEN1 mutation induces accumulation and clustering of lysosomes that, along with an increase of global p62/SQSTM1, could compromise lysosomal function and, ultimately, its degradation.
Conclusion: The findings suggest that all these modifications could eventually contribute to the neuronal degeneration that underlies the pathogenesis of Alzheimer's disease. Further research in this area may help to develop targeted therapies for the treatment of Alzheimer's disease.

Keywords:  Alzheimer’s disease; autophagy; lysosomes and mitochondria imaging; mitochondria; neurodegeneration; oxidative stress

DOI:  https://doi.org/10.3389/fnagi.2023.1087072
Anal Bioanal Chem. 2023 Jul 15.

Characterization of N-glycome profile in mouse brain tissue regions by MALDI-TOF/MS.

Yuanyuan Liu, Yutong Han, Wenjie Zhu, Qingming Luo, Jing Yuan, Xin Liu.

  Glycosylation is one of the most common types of post-translational modifications in mammals. It is well known that N-glycans play a key role in cell adhesion, differentiation, synapsis, and myelination during the development of the mammalian central nervous system (CNS). Neuropathological symptoms (such as epilepsy and Alzheimer's disease) are usually accompanied by N-glycosylation changes. In this study, we extracted N-glycan chains from eight regions of the mouse brain, and combined high-throughput, high-resolution matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MS) with the Fmoc N-hydroxysuccinimide ester (Fmoc-OSU) derivatization method to improve the sensitivity of glycan detection to characterize the total N-glycans in the mouse brain. A total of 96 N-glycan moieties were detected. An exhaustive examination of the relative abundance of N-glycans, coupled with a comparative analysis of differences, has uncovered discernible variations of statistical significance, including high mannose, fucosylated, sialylated, and galactosylated N-glycans. According to our investigations, a thorough and regionally specific cartography of glycans within the brain can facilitate the investigation of glycan-mediated mechanisms related to both the developmental trajectory and functional output of the brain. Additionally, this approach may serve as a basis for identifying potential biomarkers that are relevant to various brain-associated pathologies.

Keywords:  Derivatization; MALDI-TOF/MS; Mouse brain; N-Glycan

DOI:  https://doi.org/10.1007/s00216-023-04848-8
J Cell Sci. 2023 Jul 20. pii: jcs.260763. [Epub ahead of print]

Plasma membrane of focal adhesions has a high content of cholesterol and phosphatidylcholine with saturated acyl chains.

Hiroshi Tachibana, Kodai Minoura, Tomohiro Omachi, Kohjiro Nagao, Takafumi Ichikawa, Yasuhisa Kimura, Nozomu Kono, Yuta Shimanaka, Hiroyuki Arai, Kazumitsu Ueda, Noriyuki Kioka.

  Cellular functions, such as differentiation and migration, are regulated by the extracellular microenvironment, including the extracellular matrix (ECM). Cells adhere to ECM through focal adhesions (FAs) and sense the surrounding microenvironments. While FA proteins have been actively investigated, little is known about the lipids in the plasma membrane at FAs. In this study, we examine the lipid composition at FAs with imaging and biochemical approaches. Using a cholesterol specific probe D4 with total internal reflection fluorescence microscopy and super-resolution microscopy, we show an enrichment of cholesterol at FAs simultaneously with FA assembly. Furthermore, we establish a method to isolate the lipid from FA-rich fractions and biochemical quantification of the lipids reveals the higher content of cholesterol and phosphatidylcholine with saturated fatty acid chains in the lipids of the FA-rich fraction than in either plasma membrane fraction or the whole cell membrane. These results demonstrate that plasma membrane at FAs has a locally distinct lipid composition compared to the bulk plasma membrane.

Keywords:  Cholesterol; Focal adhesion; Lipid composition; Lipid raft

DOI:  https://doi.org/10.1242/jcs.260763
Front Cell Neurosci. 2023 ;17 1205261

Ldlr-/-.Leiden mice develop neurodegeneration, age-dependent astrogliosis and obesity-induced changes in microglia immunophenotype which are partly reversed by complement component 5 neutralizing antibody.

Florine Seidel, Kees Fluiter, Robert Kleemann, Nicole Worms, Anita van Nieuwkoop, Martien P M Caspers, Nikolaos Grigoriadis, Amanda J Kiliaan, Frank Baas, Iliana Michailidou, Martine C Morrison.

  Introduction: Obesity has been linked to vascular dysfunction, cognitive impairment and neurodegenerative diseases. However, experimental models that recapitulate brain pathology in relation to obesity and vascular dysfunction are still lacking.Methods: In this study we performed the histological and histochemical characterization of brains from Ldlr-/-.Leiden mice, an established model for obesity and associated vascular disease. First, HFD-fed 18 week-old and 50 week-old Ldlr-/-.Leiden male mice were compared with age-matched C57BL/6J mice. We then assessed the effect of high-fat diet (HFD)-induced obesity on brain pathology in Ldlr-/-.Leiden mice and tested whether a treatment with an anti-complement component 5 antibody, a terminal complement pathway inhibitor recently shown to reduce vascular disease, can attenuate neurodegeneration and neuroinflammation. Histological analyses were complemented with Next Generation Sequencing (NGS) analyses of the hippocampus to unravel molecular pathways underlying brain histopathology.
Results: We show that chow-fed Ldlr-/-.Leiden mice have more severe neurodegeneration and show an age-dependent astrogliosis that is not observed in age-matched C57BL/6J controls. This was substantiated by pathway enrichment analysis using the NGS data which showed that oxidative phosphorylation, EIF2 signaling and mitochondrial dysfunction pathways, all associated with neurodegeneration, were significantly altered in the hippocampus of Ldlr-/-.Leiden mice compared with C57BL/6J controls. Obesity-inducing HFD-feeding did not aggravate neurodegeneration and astrogliosis in Ldlr-/-.Leiden mice. However, brains from HFD-fed Ldlr-/-.Leiden mice showed reduced IBA-1 immunoreactivity and increased CD68 immunoreactivity compared with chow-fed Ldlr-/-.Leiden mice, indicating alteration of microglial immunophenotype by HFD feeding. The systemic administration of an anti-C5 treatment partially restored the HFD effect on microglial immunophenotype. In addition, NGS data of hippocampi from Ldlr-/-.Leiden mice showed that HFD feeding affected multiple molecular pathways relative to chow-fed controls: HFD notably inactivated synaptogenesis and activated neuroinflammation pathways. The anti-C5 treatment restored the HFD-induced effect on molecular pathways to a large extent.
Conclusion: This study shows that the Ldlr-/-.Leiden mouse model is suitable to study brain histopathology and associated biological processes in a context of obesity and provides evidence of the potential therapeutic value of anti-complement therapy against obesity-induced neuroinflammation.

Keywords:  aging; anti-complement component 5; astrogliosis; brain; neurodegeneration; neuroinflammation; obesity

DOI:  https://doi.org/10.3389/fncel.2023.1205261
J Inherit Metab Dis. 2023 Jul 16.

Succinic semialdehyde dehydrogenase deficiency in mice and in humans: an untargeted metabolomics perspective.

Tessa M A Peters, Udo F H Engelke, Siebolt de Boer, Joris T G Reintjes, Jean-Baptiste Roullet, Sanne Broekman, Erik de Vrieze, Erwin van Wijk, Mirjam M C Wamelink, Rafael Artuch, Ivo Barić, Jona Merx, Thomas J Boltje, Jonathan Martens, Michèl A A P Willemsen, Marcel M Verbeek, Ron A Wevers, K Michael Gibson, Karlien L M Coene.

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare neurometabolic disorder caused by disruption of the gamma-aminobutyric acid (GABA) pathway. A more detailed understanding of its pathophysiology, beyond the accumulation of GABA and gamma-hydroxybutyric acid (GHB), will increase our understanding of the disease and may support novel therapy development. To this end, we compared biochemical body fluid profiles from SSADHD patients with controls using next-generation metabolic screening (NGMS). Targeted analysis of NGMS data from cerebrospinal fluid (CSF) showed a moderate increase of aspartic acid, glutaric acid, glycolic acid, 4-guanidinobutanoic acid and 2-hydroxyglutaric acid, and prominent elevations of GHB and 4,5-dihydroxyhexanoic acid (4,5-DHHA) in SSADHD samples. Remarkably, the intensities of 4,5-DHHA and GHB showed a significant positive correlation in control CSF, but not in patient CSF. In an established zebrafish epilepsy model, 4,5-DHHA showed increased mobility that may reflect limited epileptogenesis. Using untargeted metabolomics, we identified 12 features in CSF with high biomarker potential. These had comparable increased fold changes as GHB and 4,5-DHHA. For 10 of these features, a similar increase was found in plasma, urine and/or mouse brain tissue for SSADHD compared to controls. One of these was identified as the novel biomarker 4,5-dihydroxyheptanoic acid. The intensities of selected features in plasma and urine of SSADHD patients positively correlated with the clinical severity score of epilepsy and psychiatric symptoms of those patients, and also showed a high mutual correlation. Our findings provide new insights into the (neuro)metabolic disturbances in SSADHD and give leads for further research concerning SSADHD pathophysiology. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1002/jimd.12657